Maes Hannelore, Kuchnio Anna, Carmeliet Peter, Agostinis Patrizia
a Department Cellular and Molecular Medicine; Laboratory of Cell Death and Therapy; KU Leuven ; Leuven , Belgium.
Autophagy. 2014;10(11):2082-4. doi: 10.4161/auto.36259.
Chloroquine (CQ) is exploited in clinical trials as an autophagy blocker to potentiate anticancer therapy, but it is unknown if it solely acts by inhibiting cancer cell-autonomous autophagy. Our recent study shows that besides blocking cancer cell growth, CQ also affects endothelial cells (ECs) and promotes tumor vessel normalization. This vessel normalizing effect of CQ reduces tumor hypoxia, cancer cell intravasation, and metastasis, while improving the delivery and response to chemotherapy. By compromising autophagy in melanoma cells or using mice with a conditional knockout of ATG5 in ECs, we found that the favorable effects of CQ on the tumor vasculature do not rely on autophagy. CQ-induced vessel normalization relies mainly on altered endolysosomal trafficking and sustained NOTCH1 signaling in ECs. Remarkably these CQ-mediated effects are abrogated when tumors are grown in mice harboring EC-specific deletion of NOTCH1. The autophagy-independent vessel normalization by CQ leading to improved delivery and tumor response to chemotherapy further advocates its clinical use in combination with anticancer treatments.
氯喹（CQ）在临床试验中被用作自噬阻断剂以增强抗癌治疗效果，但它是否仅通过抑制癌细胞自主自噬发挥作用尚不清楚。我们最近的研究表明，除了阻断癌细胞生长外，CQ还会影响内皮细胞（ECs）并促进肿瘤血管正常化。CQ的这种血管正常化作用可减少肿瘤缺氧、癌细胞内渗和转移，同时改善化疗药物的递送和疗效。通过抑制黑色素瘤细胞中的自噬或使用内皮细胞中条件性敲除ATG5的小鼠，我们发现CQ对肿瘤脉管系统的有利作用不依赖于自噬。CQ诱导的血管正常化主要依赖于内皮细胞中内溶酶体运输的改变和NOTCH1信号的持续激活。值得注意的是，当肿瘤在具有内皮细胞特异性缺失NOTCH1的小鼠中生长时，这些CQ介导的效应会被消除。CQ通过不依赖自噬的血管正常化作用导致化疗药物递送改善和肿瘤反应增强，这进一步支持了其与抗癌治疗联合使用的临床应用。
